@article {Zhoujpet.119.258244, author = {Xiaoyan Zhou and Eric S Muise and Robin Haimbach and Iyassu K Sebhat and Yonghua Zhu and Franklin Liu and Sandra Souza and Yanqing Kan and Shirly Pinto and David E. Kelley and Maarten Hoek}, title = {PAN-AMPK ACTIVATION IMPROVES RENAL FUNCTION IN A RAT MODEL OF PROGRESSIVE DIABETIC NEPHROPATHY}, elocation-id = {jpet.119.258244}, year = {2019}, doi = {10.1124/jpet.119.258244}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Chronic kidney disease (CKD) remains a tremendous and growing burden on the healthcare system and new therapies are needed to prevent or slow disease progression. Metabolic dysregulation and mitochondrial dysfunction are important features of acute and chronic tissue injury across species, and human genetics and preclinical data suggest that the master metabolic regulator 5{\textquoteright}-adenosine monophosphate activated protein kinase (AMPK) may be an effective therapeutic target for CKD. Merck has recently disclosed a pan-AMPK activator MK-8722 which was shown to have beneficial effects on metabolic parameters in preclinical models. In this study we investigate the effects of MK-8722 in a progressive model of diabetic nephropathy to determine whether activation of AMPK would be of therapeutic benefit. We find that MK-8722 administration in a therapeutic paradigm is profoundly reno-protective. We provide evidence that the therapeutic effects may be mediated by modulation of renal mitochondrial quality control as well as by attenuating fibrotic and lipotoxic mechanisms in kidney cells. These data further validate the concept that targeting metabolic dysregulation in CKD could be a potential therapeutic approach.SIGNIFICANCE STATEMENT Significance: We demonstrate in the present study that the pharmacological activation of AMPK using a small molecule agent provided reno-protection and improved systemic and cellular metabolism. We further indicate that modulation of renal mitochondrial quality control likely contributed to reno-protection and was distinct from the effects of enalapril. Our findings suggest that improving renal mitochondrial biogenesis and function and attenuating fibrosis and lipotoxicity by targeting key metabolic nodes could be a potential therapeutic approach in management of CKD that could complement the current standard of care.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2019/07/12/jpet.119.258244}, eprint = {https://jpet.aspetjournals.org/content/early/2019/07/12/jpet.119.258244.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }